Global Proteomic and Methylome Analysis in Human Induced Pluripotent Stem Cells Reveals Overexpression of a Human TLR3 Affecting Proper Innate Immune Response Signaling.
Cytokine
Human leukocyte antigen
Immune response
Induced pluripotent stem cells
Inflammation
MHC-I
Neural stem cells
Toll like receptor
Journal
Stem cells (Dayton, Ohio)
ISSN: 1549-4918
Titre abrégé: Stem Cells
Pays: England
ID NLM: 9304532
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
20
09
2018
revised:
17
11
2018
accepted:
21
12
2018
pubmed:
22
1
2019
medline:
21
3
2020
entrez:
22
1
2019
Statut:
ppublish
Résumé
When considering the clinical applications of autologous cell replacement therapy of human induced pluripotent stem cells (iPSC)-derived cells, there is a clear need to better understand what the immune response will be before we embark on extensive clinical trials to treat or model human disease. We performed a detailed assessment comparing human fibroblast cell lines (termed F1) reprogrammed into human iPSC and subsequently differentiated back to fibroblast cells (termed F2) or other human iPSC-derived cells including neural stem cells (NSC) made from either retroviral, episomal, or synthetic mRNA cell reprogramming methods. Global proteomic analysis reveals the main differences in signal transduction and immune cell protein expression between F1 and F2 cells, implicating wild type (WT) toll like receptor protein 3 (TLR3). Furthermore, global methylome analysis identified an isoform of the human TLR3 gene that is not epigenetically reset correctly upon differentiation to F2 cells resulting in a hypomethylated transcription start site in the TLR3 isoform promoter and overexpression in most human iPSC-derived cells not seen in normal human tissue. The human TLR3 isoform in human iPSC-NSC functions to suppress NF-KB p65 signaling pathway in response to virus (Poly IC), suggesting suppressed immunity of iPSC-derived cells to viral infection. The sustained WT TLR3 and TLR3 isoform overexpression is central to understanding the altered immunogenicity of human iPSC-derived cells calling for screening of human iPSC-derived cells for TLR3 expression levels before applications. Stem Cells 2019;37:476-488.
Identifiants
pubmed: 30664289
doi: 10.1002/stem.2966
pmc: PMC6487958
doi:
Substances chimiques
TLR3 protein, human
0
Toll-Like Receptor 3
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
476-488Informations de copyright
©2019 The Authors. Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press 2019.
Références
Epigenomics. 2009 Oct;1(1):177-200
pubmed: 22122642
BMB Rep. 2015 Dec;48(12):696-701
pubmed: 26077030
Nucleic Acids Res. 2015 Jan;43(Database issue):D447-52
pubmed: 25352553
Hum Gene Ther. 2012 Jan;23(1):56-69
pubmed: 21877920
Science. 1999 May 21;284(5418):1313-8
pubmed: 10334979
PLoS One. 2013 Jul 26;8(7):e69617
pubmed: 23922758
Nat Commun. 2014 May 30;5:3903
pubmed: 24875164
Cell. 2012 Oct 26;151(3):547-58
pubmed: 23101625
Nature. 2016 Nov 17;539(7629):437-442
pubmed: 27642729
Cell Stem Cell. 2013 Apr 4;12(4):407-12
pubmed: 23352605
N Engl J Med. 2017 Mar 16;376(11):1038-1046
pubmed: 28296613
Cell Stem Cell. 2015 Sep 3;17(3):353-9
pubmed: 26299572
Nucleic Acids Res. 2009 Jan;37(1):1-13
pubmed: 19033363
EMBO Mol Med. 2012 May;4(5):380-95
pubmed: 22407749
Nature. 2011 May 13;474(7350):212-5
pubmed: 21572395
Stem Cells. 2013 Mar;31(3):467-78
pubmed: 23225669
PLoS One. 2009 Oct 16;4(10):e7475
pubmed: 19834619
Yonsei Med J. 2004 Apr 30;45(2):359-61
pubmed: 15119015
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Stem Cell Reports. 2013 Sep 26;1(4):283-92
pubmed: 24319664
Nature. 2013 Feb 7;494(7435):100-4
pubmed: 23302801
Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):9864-9
pubmed: 12114532
Sci China Life Sci. 2014 Feb;57(2):162-70
pubmed: 24443177
Fibrogenesis Tissue Repair. 2015 May 15;8:9
pubmed: 25984235
Cell Signal. 2014 May;26(5):942-50
pubmed: 24462705
Genome Biol. 2004;5(10):R80
pubmed: 15461798
Genes Dev. 2010 Mar 15;24(6):561-73
pubmed: 20231315
Stem Cells. 2016 Feb;34(2):510-5
pubmed: 26439188
J Clin Med. 2014 Apr 04;3(2):373-87
pubmed: 26237380
Cell. 2007 Nov 30;131(5):861-72
pubmed: 18035408
J Neuroimmunol. 2005 Feb;159(1-2):12-9
pubmed: 15652398
J Clin Med. 2015 May 28;4(6):1193-206
pubmed: 26239553
Nature. 2012 Nov 29;491(7426):769-73
pubmed: 23103873
Stem Cell Reports. 2014 Jan 23;2(2):205-18
pubmed: 24527394
J Immunol. 2009 Jun 15;182(12):7963-73
pubmed: 19494321
Bioinformatics. 2008 Jul 1;24(13):1547-8
pubmed: 18467348
N Engl J Med. 2017 Aug 24;377(8):792-793
pubmed: 28834478
Nat Struct Mol Biol. 2004 Nov;11(11):1060-7
pubmed: 15502848